Angiogenesis is a fundament al process in the survival, growth and spread of cancers. In recent years several therapies have been developed to interfere with this process. Despite initial optimism these agents have rarely provided durable clinical responses. Methods capable 0f assessing angiogenesis are required to help develop effective anti-angiogenic approaches Radionuclide imaging is one potential method of assessing angiogenesis. VEGF and integrin expression are two key factors in regulation of angiogenesis in tumours and provide potential targets for radionuclide imaging of angiogenesis. This thesis investigates whether targeting of VEGF and integrins can be performed to image angiogenesis and if treatment with antiangiogenic therapy can be detected via such imaging. VEGF imaging was successfully performed by radiolabelling bevacizumab, a monoclonal antibody directed against all isoforms of VEGF, with 111 indium for SPECT imaging. This agent was validate in vitro and in vivo mouse xenograft models, and appears to bind to matrix and cell membrane associated VEGF within tumours. lntegrin imaging was attempted using 99Tc-maraciclatide, another SPECT imaging agent. This is a commercial agent based on the RGD tripeptide sequence and binds primarily to α,β3 and α,β5 integrins. It was assessed in a clinical trial and compared with histological markers of angiogenes' in patients with colorectal, renal and breast tumours. There was an inverse relationship between 99mTc•maraciclatide uptake and β13 vascular density but no correlation with other angiogenic markers. Both tracers were investigated in a preclinical xenograft model with antiangiogenic therapies Rapamycin, an mTOR inhibitor, increased uptake of 111ln-bnDTPA-bevacizumab and decrease uptake of 99"'Tc-maraciclatide. These responses corresponded with an increase in VEGF an decrease in β3 integrin levels in the tumours. Rapamycin therapy was also associated with reduction in blood vessel number and changes in perfusion as demonstrated by DCE•MRI. The effect of bevacizumab therapy on 99Tc•maraciclatide uptake was also investigated. Bevacizumab had no significant effect on either 99mTc-maraciclatide uptake or β3 integrin levels. These preliminary results demonstrate that both radiotracers have potential for imagin, angiogenesis and detecting response to angiogenic therapies. They also highlight the complex nature of the angiogenic process and that further work is necessary to determine the clinical usefulness of these agents.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:600030 |
| Date | January 2013 |
| Creators | Patel, Neel |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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